When mechanisms of immunologic tolerance to self fail, autoimmune disease can ensue. Lack of self tolerance and subsequent autoimmunity may result from the failure to delete autoreactive T cell in the thymus or periphery. The pathologic consequences of autoreactivity may be further exacerbated if the T cell makes a Th1 proinflmmatroy response (secreting gamma IFN, TNF) rather than a more benign Th2 response (secreting IL-4, IL-10). Signals mediated by the T cell receptor are critical to controling both deletion of autoreactive cells and whether specific T cells make a predominant Th1 vs Th2 response. A better understanding of the TCR signaling components and the development of animal models in which the TCR components can be qualitatively and quantitatively manipulated will aid in the development of new treatments for autoimmune disease. The zeta chain of the TCR,which has 3 activation motifs (ITAMs) in its intracytoplasmic domain, is a particularly potent signaling molecule. To study the role of zeta in T cell responses and how it may impact on autoreactivity, we have created mice in which the gene encoding zeta has been inactivated by homologous recombination (zeta-/- mice). We have also generated mice expressing transgenes encoding normal or truncated forms either of zeta (missing all three or particular ITAMs) or the gamma chain of the FcR (which is homologous to zeta) and bred these transgenes into the zeta-/- background. Results generated in the last year using mice which express transgenic TCR with defined specificties demonstrate that zeta plays a critical role in whether T cells are positively selected or tolerized in the thymus and periphery. Hence, interference with zeta signals may critically control autoreactivity. Further, there appears to be a direct correlation between the number of ITAM in the TCR and generation of tolerance. Our recent data also suggest that the tendency of T cells to make a predominant Th1 vs Th2 response is influenced by signals mediated by zeta chain. In the next year, we will apply these data to a murine model of autoimmune disease.1. Shores, E.W. and P.E. Love. 1996. Int. Rev. Immunol. (in press). 2.. Love, P.E., E.W. Shores, et. al 1994. J. Exp. Med179:1485. 3. Shores, E.W., et. al 1994. Science266:1047. 4. Combadiene et al. 1996. J.Exp.Med. 183;2109. 4. Flamand, V. Shores, E.W. et al. 1996. J. Exp Med (in press).